In 2005, Science magazine identified understanding organ regeneration as one of the top 25 unanswered questions in science. For over 400 years scientists have been studying the amazing regenerative capacity of the Axolotl or Mexican Salamander. These amazing creatures can regenerate most parts of their bodies with near perfect fidelity. However, in recent years the axolotl has lacked the rigorous genetic tools required to be an ideal model organism for the "Omics" era. Recent advances in creating the genetic tools for the Axolotl have been pioneered by members of this GO application. Using our novel tools we can now create axolotl ortholog gene arrays to match those available for mice and humans. In addition, we can engineer transgenic axolotls to define gene functions in vivo. The goal of our GO grant is to validate the axolotl as an ideal genetic organism to compare a fully regenerative vertebrate (axolotl) to mammals. No current genetic model exhibits significant regenerative capacity as an adult. The goal of Regenerative Medicine is to heighten a patient's natural regenerative capacities. No stronger tool will exist for mapping relevant genetic pathways for neural regeneration then a validated axolotl model. In the two years of this GO proposal we will directly model many of the murine models for neural regeneration of the brain and spinal cord in the axolotl, create targeted neural specific axolotl gene arrays, and contrast the genetic responses of the axolotl to the mouse in order to define the pathways of regeneration. We have already generated axolotl neural stem cell lines (Gfp+) that are undergoing initial characterization - they will be compared to mouse NSC in this proposal. We will also create a series of transgenic axolotl models to match currently existing mouse models such as GFAP:Gfp and Nestin:GFP. All of these deliverables will be made fully available to the scientific community. The goal of this Grand Opportunity proposal is to create novel research infrastructure for Regenerative Medicine. We will create the genomic tools necessary to compare the amazing regenerative capacity of the Axolotl to established mouse models of human disease. Utilizing comparative genomics will allow the identification of the pathways required for vertebrate animal regeneration as an adult.